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Background: In observational studies, matched case-control designs are routinely conducted to improve study precision. How to select covariates for match or adjustment, however, is still a great challenge for estimating causal effect between the exposure E and outcome D.Methods: From the perspective of causal diagrams, 9 scenarios of causal relationships among exposure (E), outcome (D) and their related covariates (C) were investigated. Further various simulation strategies were performed to explore whether match or adjustment should be adopted. The "do calculus" and "back-door criterion" were used to calculate the true causal effect (β) of E on D on the log-odds ratio scale. 1:1 matching method was used to create matched case-control data, and the conditional or unconditional logistic regression was utilized to get the estimators ([Formula: see text]) of causal effect. The bias ([Formula: see text]) and standard error ([Formula: see text]) were used to evaluate their performances.Results: When C is exactly a confounder for E and D, matching on it did not illustrate distinct improvement in the precision; the benefit of match was to greatly reduce the bias for β though failed to completely remove the bias; further adjustment for C in matched case-control designs is still essential. When C is associated with E or D, but not a confounder, including an independent cause of D, a cause of E but has no direct causal effect on D, a collider of E and D, an effect of exposure E, a mediator of causal path from E to D, arbitrary match or adjustment of this kind of plausible confounders C will create unexpected bias. When C is not a confounder but an effect of D, match or adjustment is unnecessary. Specifically, when C is an instrumental variable, match or adjustment could not reduce the bias due to existence of unobserved confounders U.Conclusions: Arbitrary match or adjustment of the plausible confounder C is very dangerous before figuring out the possible causal relationships among E, D and their related covariates. [ABSTRACT FROM AUTHOR]

Background: In stark contrast to network-centric view for complex disease, regression-based methods are preferred in disease prediction, especially for epidemiologists and clinical professionals. It remains a controversy whether the network-based methods have advantageous performance than regression-based methods, and to what extent do they outperform.Methods: Simulations under different scenarios (the input variables are independent or in network relationship) as well as an application were conducted to assess the prediction performance of four typical methods including Bayesian network, neural network, logistic regression and regression splines.Results: The simulation results reveal that Bayesian network showed a better performance when the variables were in a network relationship or in a chain structure. For the special wheel network structure, logistic regression had a considerable performance compared to others. Further application on GWAS of leprosy show Bayesian network still outperforms other methods.Conclusion: Although regression-based methods are still popular and widely used, network-based approaches should be paid more attention, since they capture the complex relationship between variables. [ABSTRACT FROM AUTHOR]

Background: Confounders can produce spurious associations between exposure and outcome in observational studies. For majority of epidemiologists, adjusting for confounders using logistic regression model is their habitual method, though it has some problems in accuracy and precision. It is, therefore, important to highlight the problems of logistic regression and search the alternative method.Methods: Four causal diagram models were defined to summarize confounding equivalence. Both theoretical proofs and simulation studies were performed to verify whether conditioning on different confounding equivalence sets had the same bias-reducing potential and then to select the optimum adjusting strategy, in which logistic regression model and inverse probability weighting based marginal structural model (IPW-based-MSM) were compared. The "do-calculus" was used to calculate the true causal effect of exposure on outcome, then the bias and standard error were used to evaluate the performances of different strategies.Results: Adjusting for different sets of confounding equivalence, as judged by identical Markov boundaries, produced different bias-reducing potential in the logistic regression model. For the sets satisfied G-admissibility, adjusting for the set including all the confounders reduced the equivalent bias to the one containing the parent nodes of the outcome, while the bias after adjusting for the parent nodes of exposure was not equivalent to them. In addition, all causal effect estimations through logistic regression were biased, although the estimation after adjusting for the parent nodes of exposure was nearest to the true causal effect. However, conditioning on different confounding equivalence sets had the same bias-reducing potential under IPW-based-MSM. Compared with logistic regression, the IPW-based-MSM could obtain unbiased causal effect estimation when the adjusted confounders satisfied G-admissibility and the optimal strategy was to adjust for the parent nodes of outcome, which obtained the highest precision.Conclusions: All adjustment strategies through logistic regression were biased for causal effect estimation, while IPW-based-MSM could always obtain unbiased estimation when the adjusted set satisfied G-admissibility. Thus, IPW-based-MSM was recommended to adjust for confounders set. [ABSTRACT FROM AUTHOR]

Background and purpose: Previous studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation. Methods: Summary statistics from the ISGC (case = 10,307 and control = 19,326) were used as ischemic stroke genetic instruments, AFGen Consortium data (case = 65,446 and control = 522,744) were used for atrial fibrillation, and other consortia data were used for potential mediators (fasting insulin, white blood cell count, procalcitonin, systolic and diastolic blood pressure, body mass index, waist circumference, and height). Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect. Results: Blood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; P = 1.3 × 10−5). One-unit increase of genetically determined ischemic stroke was associated with 0.02 (DBP: 95% CI, 0.001 to 0.034, P = 0.029; SBP: 95% CI, 0.006 to 0.034, P = 0.003) upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk (DBP: RR, 1.18; 95% CI, 1.03 to 1.35; P = 0.012. SBP: RR, 1.18; 95% CI, 1.01 to 1.38; P = 0.04). Specially, we also found the bidirectional causality between blood pressure and ischemic stroke. Conclusions: Our study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients. [ABSTRACT FROM AUTHOR]

Background: In observational studies, matched case-control designs are routinely conducted to improve study precision. How to select covariates for match or adjustment, however, is still a great challenge for estimating causal effect between the exposure E and outcome D., Methods: From the perspective of causal diagrams, 9 scenarios of causal relationships among exposure (E), outcome (D) and their related covariates (C) were investigated. Further various simulation strategies were performed to explore whether match or adjustment should be adopted. The "do calculus" and "back-door criterion" were used to calculate the true causal effect (β) of E on D on the log-odds ratio scale. 1:1 matching method was used to create matched case-control data, and the conditional or unconditional logistic regression was utilized to get the estimators ([Formula: see text]) of causal effect. The bias ([Formula: see text]) and standard error ([Formula: see text]) were used to evaluate their performances., Results: When C is exactly a confounder for E and D, matching on it did not illustrate distinct improvement in the precision; the benefit of match was to greatly reduce the bias for β though failed to completely remove the bias; further adjustment for C in matched case-control designs is still essential. When C is associated with E or D, but not a confounder, including an independent cause of D, a cause of E but has no direct causal effect on D, a collider of E and D, an effect of exposure E, a mediator of causal path from E to D, arbitrary match or adjustment of this kind of plausible confounders C will create unexpected bias. When C is not a confounder but an effect of D, match or adjustment is unnecessary. Specifically, when C is an instrumental variable, match or adjustment could not reduce the bias due to existence of unobserved confounders U., Conclusions: Arbitrary match or adjustment of the plausible confounder C is very dangerous before figuring out the possible causal relationships among E, D and their related covariates.

Background: In stark contrast to network-centric view for complex disease, regression-based methods are preferred in disease prediction, especially for epidemiologists and clinical professionals. It remains a controversy whether the network-based methods have advantageous performance than regression-based methods, and to what extent do they outperform., Methods: Simulations under different scenarios (the input variables are independent or in network relationship) as well as an application were conducted to assess the prediction performance of four typical methods including Bayesian network, neural network, logistic regression and regression splines., Results: The simulation results reveal that Bayesian network showed a better performance when the variables were in a network relationship or in a chain structure. For the special wheel network structure, logistic regression had a considerable performance compared to others. Further application on GWAS of leprosy show Bayesian network still outperforms other methods., Conclusion: Although regression-based methods are still popular and widely used, network-based approaches should be paid more attention, since they capture the complex relationship between variables.

Background: We propose a novel Markov Blanket-based repeated-fishing strategy (MBRFS) in attempt to increase the power of existing Markov Blanket method (DASSO-MB) and maintain its advantages in omic data analysis., Results: Both simulation and real data analysis were conducted to assess its performances by comparing with other methods including χ(2) test with Bonferroni and B-H adjustment, least absolute shrinkage and selection operator (LASSO) and DASSO-MB. A serious of simulation studies showed that the true discovery rate (TDR) of proposed MBRFS was always close to zero under null hypothesis (odds ratio = 1 for each SNPs) with excellent stability in all three scenarios of independent phenotype-related SNPs without linkage disequilibrium (LD) around them, correlated phenotype-related SNPs without LD around them, and phenotype-related SNPs with strong LD around them. As expected, under different odds ratio and minor allel frequency (MAFs), MBRFS always had the best performances in capturing the true phenotype-related biomarkers with higher matthews correlation coefficience (MCC) for all three scenarios above. More importantly, since proposed MBRFS using the repeated fishing strategy, it still captures more phenotype-related SNPs with minor effects when non-significant phenotype-related SNPs emerged under χ(2) test after Bonferroni multiple correction. The various real omics data analysis, including GWAS data, DNA methylation data, gene expression data and metabolites data, indicated that the proposed MBRFS always detected relatively reasonable biomarkers., Conclusions: Our proposed MBRFS can exactly capture the true phenotype-related biomarkers with the reduction of false negative rate when the phenotype-related biomarkers are independent or correlated, as well as the circumstance that phenotype-related biomarkers are associated with non-phenotype-related ones.

Background: The genetic variants identified by Genome-wide association study (GWAS) can only account for a small proportion of the total heritability for complex disease. The existence of gene-gene joint effects which contains the main effects and their co-association is one of the possible explanations for the "missing heritability" problems. Gene-gene co-association refers to the extent to which the joint effects of two genes differ from the main effects, not only due to the traditional interaction under nearly independent condition but the correlation between genes. Generally, genes tend to work collaboratively within specific pathway or network contributing to the disease and the specific disease-associated locus will often be highly correlated (e.g. single nucleotide polymorphisms (SNPs) in linkage disequilibrium). Therefore, we proposed a novel score-based statistic (SBS) as a gene-based method for detecting gene-gene co-association., Results: Various simulations illustrate that, under different sample sizes, marginal effects of causal SNPs and co-association levels, the proposed SBS has the better performance than other existed methods including single SNP-based and principle component analysis (PCA)-based logistic regression model, the statistics based on canonical correlations (CCU), kernel canonical correlation analysis (KCCU), partial least squares path modeling (PLSPM) and delta-square (δ (2)) statistic. The real data analysis of rheumatoid arthritis (RA) further confirmed its advantages in practice., Conclusions: SBS is a powerful and efficient gene-based method for detecting gene-gene co-association.

Background: Hand, foot, and mouth disease (HFMD) is the most common communicable disease in China. Shandong Province is one of the most seriously affected areas. The distribution of HFMD had spatial heterogeneity and seasonal characteristic in this setting. The aim of this study was to explore the associations between climate and HFMD by a Bayesian approach from spatio-temporal interactions perspective., Methods: The HFMD data of Shandong Province during 2008-2012 were derived from the China National Disease Surveillance Reporting and Management System. And six climatic indicators were obtained from the Meteorological Bureau of Shandong Province. The global spatial autocorrelation statistic (Moran's I) was used to detect the spatial autocorrelation of HFMD cases in each year. The optimal one among four Bayesian models was further adopted to estimate the relative risk of the occurrence of HFMD via Markov chain Monte Carlo., Results: The annual average incidence rate of HFMD was 104.40 per 100,000 in Shandong Province. Positive spatial autocorrelation appeared at county level (Moran's I≥0.30, P<0.001). The best fitting Spatio-temporal interactive model showed that annual average temperature, annual average pressure, annual average relative humidity, annual average wind speed and annual sunshine hours were significantly positive related to the occurrence of HFMD. The estimated relative risk of 36, 87, 91, 79, 65 out of 140 counties for 2008-2012 respectively were significantly more than 1., Conclusions: There were obvious spatio-temporal heterogeneity of HFMD in Shandong Province, and the climatic indicators were associated with the epidemic of HFMD. Bayesian approach should be recommended to capture the spatial-temporal pattern of HFMD.